Eosinophils play an important role in the pathogenesis of asthma. Both asthma severity and extent of airway hyperresponsiveness correlate with numbers of blood and sputum eosinophils. Bronchial biopsy studies show that eosinophils are a prominent component of asthmatic airway inflammation and that eosinophil granule contents are present in increased concentrations in the airway lining fluid of asthmatics. These granule contents consist of a number of proteins that have direct toxic effects on airway cells through multiple mechanisms such as epithelial cell sloughing, ciliostasis, generation of oxygen radicals and injury of airway nerve fibers. Eosinophils also produce mediators that can augment mast cell histamine release. This spectrum of activities contributes directly to chronic inflammation of the bronchial airway as manifested by swelling of the airway walls and the generation of airway mucus. By facilitating the penetration of airborne agents through the damaged airway epithelium, this inflammation can directly cause increased neuronal responsiveness and smooth muscle contraction (Greenfeder et al., Respiratory Research 2:71–79, 2001).
Interleukin-5 (IL-5) is a major eosinophil mediator and a critical factor in inflammatory injury of the airways in asthma. It is produced primarily by the Th2 subset of T cells and, to a lesser extent, by other cell types including eosinophils. IL-5 is of critical importance for the maturation of eosinophils in the bone marrow and of minor importance for the chemotactic response of eosinophils. IL-5 also stimulates eosinophil activation, prolongs survival, facilitates degranulation in response to specific stimuli (such as IgA or IgG), and is generally a pro-inflammatory mediator. Increased levels of IL-5 have been measured in clinical asthma and human bronchial antigen challenge models (Greenfeder et al., Respiratory Research 2:71–79, 2001).
Asthma is currently most effectively treated by a regimen of either inhaled or oral steroids that suppress expression of a number of key mediators in asthma, including IL-5, resulting in decreased pulmonary inflammation. There are, however, perceived long-term liabilities of steroid therapy. For these reasons, direct anti-IL-5 therapy is an attractive target in the management of asthma.
Thus, it would be desirable to obtain high-affinity antibodies, particularly human anti-IL-5 antibodies, that could be used to treat Il-5 mediated pathologies in humans.